The present invention relates to novel compositions of matter and methods for using them as pharmaceutical agents. More particularly, the present invention relates to novel solutions of certain relatively unstable prostaglandins (prostaglandin E compounds), known to be useful for a wide variety of pharmacological purposes. Most particularly, the present invention relates to gelled solutions of these E-type prostaglandins wherein the gelling agent is colloidal silicon dioxide and the solvent within which said prostaglandin E compound is dissolved is an organic solvent, especially triacetin.
Prostaglandins are a family of cyclopentane-containing fatty acids. Typically these cyclopentane derivatives contain two side chains attached to adjacent positions of the cyclopentane ring (C-8 and C-12) in a trans configuration with respect to one another. In the natural prostaglandins the side chain at C-8 is carboxyl-terminated, contains seven carbon atoms and is attached in the .alpha.-configuration when this side chain is drawn in the conventional manner. The C-12 side chain is .omega.-alkyl terminated, substituted at C-15 by an .alpha.-hydroxyl group and attached in the .beta. configuration. The carbon atoms of the cyclopentane ring adjacent to the attachment of these side chains are substituted with oxygenated functional groups in the PGE compounds. Specifically, in the naturally occurring PGE compounds the carboxyl-terminated side chain is attached to the cyclopentane ring at a position adjacent to an oxo group, while the position adjacent to the other side chain is substituted by an hydroxyl group. Hence, prostaglandin E.sub.2 can be represented by the structure of formula I in which carbon atom numbering is given. For a more complete description of the PGE compounds, refer to the definition of "prostaglandin-like compounds of the PGE-type" set forth in U.S. Pat. No. 3,966,962, incorporated here by reference. Accordingly, the PGE compounds, i.e., the .beta.-hydroxy ketones, includes such substances as PGE.sub.2, PGE.sub.1, 15-methyl-PGE.sub.2, (15R)-15-methyl-PGE.sub.2, 16,16-dimethyl-PGE.sub.2, 17-phenyl-18,19,20-trinor-PGE.sub.2, 16-phenoxy-17,18,19,20-tetranor-PGE.sub.2, 15-cyclohexyl-16,17,18,19,20-pentanor-PGE.sub.2, (11S),20-dimethyl-PGE.sub.2, and the like.
The use of organic solvents, especially dry organic solvents, as a means of stabilizing PGE compounds is likewise known in the art. For example, U.S. Pat. No. 3,966,962, referred to above, discloses the use of glyceryl triacetate or triacetin as a stabilizing solvent for PGE.sub.2 and similar PGE compounds.
Dipolar aprotic solvents such as N,N-dimethylacetamide (DMA), are also known stabilizers of PGE compounds. See U.S. Pat. No. 3,829,579. In addition to these organic solvents, other materials such as triethyl citrate have demonstrated an ability to stabilize PGE compounds. See U.S. Pat. No. 4,211,793.
Protic organic solvents are also known stabilizers of PGE compounds. In this regard, alcohols and glycols are known to be useful stabilizing solvents. See U.S. Pat. No. 3,749,800. See also U.S. Pat. No. 3,927,197, describing tertiary alcohol stabilization of PGE compounds.
In addition to the use of organic solvents for the stabilization of prostaglandins, further known in the art are hydrophylic gels, especially starchy gels which stabilize PGE compounds embedded there within. In this regard, cyclodextrin clathrates, especially .beta.-cyclodextrin clathrates are known as stabilizers for PGE compounds. See U.S. Pat. No. 3,816,393.
See also Calder, A. A. et al., "Ripening of a Cervix with Extra Amniotic Prostaglandin E.sub.2 in Viscous Gel Before Induction of Labor", British Journal of Obstetrics and Gynecology 84:264-268 (1977) which describes the use of hydroxyethyl methyl cellulose as a gelling agent for PGE.sub.2. Moreover the use of gelled cellulose as a stabilizing agent for PGE.sub.2 is described in Derwent Farmdoc CPI No. 91634B/51, abstracting Japanese Kokai No. 143,516, published Nov. 8, 1979.
Besides starchy materials, polymeric materials have also been reported to be effective solid or gelled stabilizing agents for for example, the use of polyvinyl pyrolidone (PVP) to stabilize prostaglandin E compounds is reported in U.S. Pat. No. 3,826,823. See also the use of polyethylene oxide cross linked with urethane group for prostaglandin formulation described in European published application Nos. 16,652 and 16,654. Finally see also the carbohydrate polymer or cross linked carbohydrate polymers described in Derwent Farmdoc CIP No. 43291C/25 abstracting Belgian Pat. No. 881,351.
The use of colloidal silica dioxide as a gelling agent for organic solvents is also known. See Eros, I., et al, "Applications of Colloidal Silicon Dioxide in Pharmaceutical Technology, II, Gel-forming Properties of Aerosil", Gysgyszereszet 19(8), 290-5 (1975); Chem. Abstracts 83:183331q (1975). In particular the use of colloidal silica dioxide with organic solvents for preparing gels containing pharmaceutically active materials is also known. See M. Sherriff and R. P. Enever, "Rheological and Drug Release Properties of Oil Gels Containing Coloidal Silicon Dioxide," J. Pharm. Sci., 68(7), 842-5 (1979).